The long term objectives of this research are to elucidate biochemical mechanisms that are involved in the transmission of signals from growth factor receptors to various parts of the cell. Of particular interest are the pathways of communication between receptors that possess protein tyrosine kinase activity and the large family of kinases and phosphatases that are involved in protein serine/threonine phosphorylation- dephosphorylation. Based on the concept that many of the effects of protein tyrosine phosphorylation in general are made manifest through changes in the state of protein serine/threonine phosphorylation, it is anticipated that this research will provide information relating not only to receptor function but also to the cellular functions of oncogene-encoded protein tyrosine kinases. An important goal of this research will be the identification of messenger-independent protein serine/threonine kinases and phosphatases whose activities are changed by growth factors through mechanisms involving protein phosphorylation-dephosphorylation. These enzymes will be purified and characterized so that they can be utilized in turn as substrates to seek out enzymes responsible for changing their activities; i.e. a "more proximal" set of kinases or phosphatases. By this approach it is hoped that potential cascade systems responsible for signal transmission can be detected and characterized. Preliminary work in this laboratory and elsewhere has resulted in the identification of several specific protein serine/threonine kinases that undergo activation in response to growth factors and will serve as the point of departure for this research. These include casein kinase II, ribosomal protein S6 kinase, several "S6 peptide" kinases, a myelin basic protein kinase, and a form of protein phosphatase 1. The reaction mechanisms involved in the activation of these enzymes will be determined. In addition to focusing in the mechanisms of activation of casein kinase II, which is one of the kinases activated by growth factors, this project will also encompass a more comprehensive study involving the molecular properties, specificity, cellular localization and cellular targets of this particular enzyme. Studies on the mechanism of activation of glycogen synthase will be used as model system in which to test the physiological significance of phosphorylation-dephosphorylation cascades revealed by this research. It is hoped that the results of this research will increase our knowledge of metabolic regulation and provide information useful in the understanding of diabetes and related disorders.